The present invention relates to methods for preparing (S)-N-tert-butyl-1,2,3,4-tetrahydro-3-isoquinoline-carboxamide ("tic-c"), and (S)-decahydroisoquinoline-3-carboxylic acid t-butylamide ("tic-d"), key intermediates in the synthesis of known compounds having pharmaceutical activity. (Tic-d is also referred to as (S)-decahydroisoquinoline-3-carboxylic acid-tert-butylamide in the prior art).
Martin et al, U.S. Pat. No. 5,196,438, describes certain amino acid derivatives which inhibit proteases of viral origin, and which can be used in the treatment of viral infections caused by HIV and other retroviruses. The compounds disclosed by Martin et al have the structural formula: ##STR1## Martin et al have demonstrated that these compounds have in vitro antiviral activity.
Martin et al's synthesis of the above amino acid derivatives involves a step wherein a compound having the formula ##STR2## where R' is an amino-protecting group and X is chloride or bromide, is reacted with tic-d: ##STR3##
A process for synthesizing tic-d from phenethylamine derivatives is described in EPO Application 0 533 000 A1 (Gokhale et al, published Mar. 24, 1993). The phenethylamine derivatives which are used in the Gokhale et al synthesis can be formed by reacting N-benzyloxycarbonyl-L-phenylalanine with N-ethyl morpholine and isobutyl chloroformate. The resultant phenethylamine derivative has the general formula: ##STR4## wherein Z is benzyloxycarbonyl and R" can be lower alkylamino. When the forgoing phenethylamine derivative is reacted with formaldehyde or dimethoxymethane in the presence of sulfuric acid in acetic acid, an isoquinoline compound is formed: ##STR5## Gokhale et al show that this compound can be transformed to a 1,2,3,4-tetrahydro-2-isoquinoline derivative having the general formula: ##STR6## wherein R can be tert-butyl amino. When R is so defined, the compound is systematically named, (S)-N-tert-butyl-1,2,3,4-tetrahydro-3-isoquinoline carboxamide ("tic-c"). Gokhale et al state that tic-c, in turn, can be hydrogenated to tic-d, which can be used in the manufacture of protease inhibitors.
A synthesis of the hydrochloride salt of tic-c is reported in E. C. Weir et al, "Tricyclic Hydantoins and Thiohydantoins of Phenylalanine," Ch. Chron., Vol. 18, No. 1, pp. 1-17 (March, 1989). The compound was formed by reacting t-butyl amine with a tri-cyclic N-carboxyanhydride: ##STR7## The reaction reported by Weir et al was run in a chloroform solvent; yield of tic-c was reported as 57% (id., Table IV).
The disadvantages of the above processes are: 1) the procedure requires a chlorinated solvent; 2) the yield of desired tic-c product is not good; 3) the process uses PCl.sub.5 ; and 4) the transformation of tic-a to tic-c requires three steps.